title: Early human prostate adenocarcinomas harbor androgen-independent cancer cells.
abstract: Although blockade of androgen receptor (AR) signaling represents the main treatment for advanced prostate cancer (PrCa), many patients progress to a lethal phenotype of "Castration-Resistant" prostate cancer (CR-PrCa). With the hypothesis that early PrCa may harbor a population of androgen-unresponsive cancer cells as precursors to CR-recurrent disease, we undertook the propagation of androgen-independent cells from PrCa-prostatectomy samples of early, localized (Stage-I) cases. A collection of 120 surgical specimens from prostatectomy cases was established, among which 54 were adenocarcinomas. Hormone-free cell culture conditions were developed allowing routine propagation of cells expressing prostate basal cell markers and stem/progenitor cell markers, and which proliferated as spheres/spheroids in suspension cultures. Colonies of androgen-independent epithelial cells grew out from 30/43 (70%) of the adenocarcinoma cases studied in detail. Fluorescence microscopy and flow cytometry showed that CR-PrCa cells were positive for CD44, CD133, CK5/14, c-kit, integrin α2β1, SSEA4, E-Cadherin and Aldehyde Dehydrogenase (ALDH). All 30 CR-PrCa cell cultures were also TERT-positive, but negative for TMPRSS2-ERG. Additionally, a subset of 22 of these CR-PrCa cell cultures was examined by orthotopic xenografting in intact and castrated SCID mice, generating histologically typical locally-invasive human PrCa or undifferentiated cancers, respectively, in 6-8 weeks. Cultured PrCa cells and orthotopically-induced in vivo cancers lacked PSA expression. We report here the propagation of Cancer Initiating Cells (CIC) directly from Stage I human PrCa tissue without selection or genetic manipulation. The propagation of stem/progenitor-like CR-PrCa cells derived from early human prostate carcinomas suggests the existence of a subpopulation of cells resistant to androgen-deprivation therapy and which may drive the subsequent emergence of disseminated CR-PrCa.
authors.affiliation: Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Rita R
authors.initials: RR
authors.lastname: Fiñones
authors.forename: Jo
authors.initials: J
authors.lastname: Yeargin
authors.forename: Melissa
authors.initials: M
authors.lastname: Lee
authors.forename: Aman Preet
authors.initials: AP
authors.lastname: Kaur
authors.forename: Clari
authors.initials: C
authors.lastname: Cheng
authors.forename: Paulina
authors.initials: P
authors.lastname: Sun
authors.forename: Christopher
authors.initials: C
authors.lastname: Wu
authors.forename: Catherine
authors.initials: C
authors.lastname: Nguyen
authors.forename: Jessica
authors.initials: J
authors.lastname: Wang-Rodriguez
authors.forename: April N
authors.initials: AN
authors.lastname: Meyer
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Baird
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Donoghue
authors.forename: Martin
authors.initials: M
authors.lastname: Haas
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002369:Castration; D002452:Cell Count; D049109:Cell Proliferation; D048430:Cell Shape; D003094:Collagen; D004338:Drug Combinations; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin; D008297:Male; D051379:Mice; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D011509:Proteoglycans; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D014408:Biomarkers, Tumor; D004338:Drug Combinations; D007797:Laminin; D015514:Oncogene Proteins, Fusion; D011509:Proteoglycans; C515553:TMPRSS2-ERG fusion protein, human; C059485:matrigel; D003094:Collagen; D000444:Aldehyde Dehydrogenase